Measles is a negative-stranded RNA virus belonging to the genus Morbillivirus. The measles virus is highly contagious in its human host and is disseminated by coughing and sneezing from an infected host. The virus enters the bloodstream, spreads through the body and infects lymphoid tissues. A period of infectivity persists from approximately 6-7 days prior to appearance of a rash through about 2-3 days subsequent to appearance of the rash. Prodromal symptoms of fever and malaise occur about 10 days subsequent to exposure. This is followed by a hacking cough, coryza, conjunctivitis, and possibly hotophobia. Koplik spots appear approximately 2 days prior to appearance of the rash. The stage of maximal severity of the infection the patient may complain of headaches, abdominal pain, vomiting, diarrhea, and/or myalgia.
Mumps is a negative-stranded RNA virus belonging to the genus Paramyxovirus. The incubation period for the mumps virus is usually 17-21 days, but may range from 8 to 37 days. After infection and growth in the respiratory tract, the virus enters the bloodstream where it is systemically delivered to various body tissues. Mumps is characterized by swelling and tenderness of the parotid gland and occasionally through other salivary glands. Prior to swelling the patient may experience pain behind the jaw and just below the ear, which is increased by pressure and movement of the jaws. More severe cases may include prodromal symptoms such as anorexia, headache, vomiting, myaglia and high fever.
Rubella virus is a positive-stranded RNA virus and sole member of family Togaviridae which causes german measles. Rubella infection usually occurs by airborne spread of infected droplets. Many rubella infections are sub clinical, with a ratio of approximately 2:1 of in apparent to overt disease. The incubation period for rubella virus is 14-21 days, with a characteristic pattern of adenopathy, rash and low grade fever. Rubella during early pregnancy frequently results in fetal infection, which may be chronic and may produce a spectrum of illness known as Congenital Rubella Syndrome (CRS).
Chickenpox (varicella-zoster) virus is a herpes virus, which are a group of intranuclear, double-stranded DNA viruses that can establish a latent infection many years after a primary infection. Chickenpox is one of the most common and highly communicable diseases and occurs primarily in childhood. A rash is observed generally over the entire body together with an attack of fever which occurs after an incubation period running between 14 and 17 days. The disease results in a muscular rash which may, in many cases, form pustules and, in extreme cases, leave scars. Other complications such as central nervous system disturbance, myelitis and neuritis were known to occur as results from chickenpox. A live attenuated vaccine and a process for making the vaccine is known for chickenpox and is disclosed in U.S. Pat. No. 3,985,615, issued to Kubo.
For the past several decades a routine vaccination schedule for infants and children has included immunization with a live attenuated trivalent vaccine for measles, mumps and rubella at approximately 15 months of age and again sometime between ages 4 through 6 or at middle school age. Also available to the public are various monovalent (e.g., measles, mumps, rubella or chicken pox), divalent (e.g., measles-mumps) and tetravalent (e.g., measles-mumps-rubella-chicken pox) vaccines.
Vaccine stabilizers are well known in the art as chemical compounds added to a vaccine formulation to enhance vaccine stability during low temperature storage or storage post-lyophilization.
One such chemical stabilizer is referred to as SPGA and is described in Bovarnick et al., 1950, J. Bact. 59:509-522. One liter of SPGA was disclosed to contain 0.218M sucrose (74.62 g), 0.00376 M KH.sub.2 PO.sub.4 (0.52 g), K.sub.2 HPO.sub.4 0.0071 M (1.25 g), potassium glutamate 0.0049 M (0.912 g) and 1% serum albumin (10g).
U.S. Pat. No. 3,783,098, issued to Calnek, et al., discloses a modification of SPGA wherein monosodium glutamate is substituted for monopotassium glutamate. Also, use of a starch hydrosylate such as glucose or dextran maybe substituted wholly or partly for sucrose. Finally, casein or PVP may be substituted wholly or partly for albumin as described (see also U.S. Pat. No. 3,915,794, issued to Zygrsich, et al.).
U.S. Pat. No. 4,000,256, issued to Hilleman, et al., describes an SPGA stabilizer containing per liter of sterile distilled water: 74.62 g sucrose, 0.45g KH.sub.2 PO.sub.4, 1.35 g K.sub.2 HP.sub.04, 0.956 g monosodium L-glutamate, and 40 ml of a 25% solution of human albumin.
In general, an SPGA stabilizer contains from about 2 to about 10% of a particular sugar, (e.g., sucrose), from about 0.05 to about 0.3% of a mono- or dibasic alkali metal phosphate salt or mixture thereof, e.g., KH.sub.2 PO.sub.4, K.sub.2 HPO.sub.4, NaH.sub.2 PO.sub.4 or Na2HPO.sub.4, from about 0.05 to about 0.2% of a glutamic acid alkali metal salt, e.g., sodium or potassium glutamate; and from about 0.5% to about 2% serum albumin, e.g., bovine serum albumin or human albumin.
Another chemical stabilizer known in the art comprises hydrolyzed gelatin, Medium O and sorbitol. This chemical stabilizer, disclosed in U.S. Pat. No. 4,147,772, issued to McAleer, et al., comprises approximately 3.5% hydrolyzed gelatin, 3.5% sorbitol, 1.0% Medium 199, along with minimal amounts of sodium bicarbonate and phenol red.
A vaccine stabilizer modified from U.S. Pat. No. 4,147,772 is disclosed in U.S. Pat. No. 4,273,762, issued to McAleer, et al. This stabilizer comprises the components disclosed in U.S. Pat. No. 4,147,772 as well as minute amounts of DPG solution, which contains, among other compounds, cysteine, glutathionine, ascorbic acid, vitamin A and USP.
Despite theses advances in the area of vaccine formulations, there remains a distinct need for live vaccine formulations with improved thermostability and shelf-life, especially live measles, mumps and rubella vaccines. None of the prior art stabilizers impart the desired enhanced sustained level of stability. The present invention addresses and meets the long felt need for a stabilizer and live vaccine formulation with increased thermostability subsequent to lyophilization.